The objective of the proposed research is to target BMP signaling as a therapy for melanoma. Recent data indicate that BMP signaling in melanomas is driven by the BMP ligand GDF6, which becomes expressed in melanoma cells during the tumorigenic process. Inhibition of GDF6 kills melanoma cells in vitro and abrogates tumor growth in vivo. The presence of high GDF6 expression in patient tumors is correlated with metastatic progression and low survival. Taken together, these data indicate that targeting GDF6 could be an effective melanoma therapy. GDF6 acts as an extracellular ligand, and a panel of monoclonal antibodies that recognize the mature, secreted form of GDF6 has been generated. This panel of monoclonals will be assessed for specific binding and anti-tumor efficacy in two aims. In the first aim, anti-GDF6 monoclonals will be epitope- mapped and their binding affinities measured. In addition, their ability to bind cell surface receptors will be assessed as will their ability to kill melanoma cells in vitro. In the second aim, monoclonals with the best binding and in vitro efficacy profiles will be tested for their effects on tumor growth in vivo. Sufficient quantities of monoclonals will be produced for injections into tumor-bearing mice. Xenografts will be created and monoclonals injected to determine if these anti-GDF6 antibodies can cause tumor regression on their own as well as in cooperation with current standard therapies. The proposed studies will be the first targeting of BMP signaling in melanoma and represent an orthogonal approach to complement existing small molecule and immunotherapies, which benefit only a subset of late-stage melanoma patients and often do so only transiently. Establishing efficacy of anti-GDF6 antibodies in the proposed studies would serve as a springboard to making humanized versions and clinical testing of such antibodies.